Patients with rheumatoid arthritis (RA) have increased cardiovascular mortality. TNF-α is a critical mediator of inflammation and metabolic response in patients with RA. Increased insulin resistance and dyslipidemia were known risk factors in patients with active RA, however, the regulation of these metabolic parameters by TNF-α is poorly understood. Neutralization of TNF-α with infliximab offers a unique opportunity to study TNF-α-mediated regulation of these metabolic parameters in RA. The aim of the study was to assess the in vivo TNF-α-mediated regulation of insulin resistance and lipids levels in RA. Nineteen patients with active RA treated with infliximab were prospectively followed for 14 weeks. Plasma lipids levels and insulin resistance were measured at baseline, 6 and 14 weeks after infliximab treatment. At week 14, the disease activity (DAS-28 score) improved significantly (p < 0.000), with a significant reduction in both C-reactive protein (p = 0.007) and erythrocyte sedimentation rate (p = 0.006) levels. The body weight did not change during the study period. After infliximab treatment, insulin resistance improved as reflected by the significant reduction in the Homeostasis Model Assessment Index. Total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and apolipoprotein B (apoB) levels all increased significantly from baseline. Nonetheless, the atherogenic index, LDL-cholesterol/HDL-cholesterol ratio, and the LDL/apoB ratio remained unchanged. Infliximab improves insulin sensitivity and alters lipid profile in patients with active RA.